Among all atherosclerotic lesions, vulnerable plaque is particularly lethal and its sudden rupture typically leads to intraluminal thrombus, directly linked to a variety of clinical manifestations such as stroke and acute coronary syndromes. These rupture-prone plaques usually consist of a large lipid-rich core in the central portion of the eccentrically thickened intima and a thin fibrous cap. Reliable, noninvasive imaging tools are needed to identify these potentially fatal plaques before their disruption. We have developed a technique, called microwave-induced thermal imaging (MITI), to image tissue dielectric and thermal properties with potentially high spatial and contrast resolution. Under a reasonable set of assumptions, the imaging parameter is simply the product of the microwave absorption coefficient (alpha) with the derivative of the sound speed with respect to temperature (lambda). Generally, water-bearing tissue can be easily distinguished from lipids based on lambda, which can be particularly valuable in plaque composition characterization and vulnerability assessment. Consequently, we rename MITI thermal strain imaging (TSI) to indicate our new focus on the imaging parameter lambda in the model. This also allows us to explore other energy delivery methods in addition to microwaves without degrading system performance. We propose to test TSI for high-risk plaque identification in peripheral arteries, especially the carotid. If successful, it will represent a high performance, cost-effective, noninvasive alternative to current techniques such as IVUS, OCT, ultrafast computed tomography (UFCT) and magnetic resonance imaging (MRI). This revised R21 application presents a plan to test TSI as a potentially noninvasive, simple, and cheap imaging tool providing information about arterial plaque vulnerability with high spatial and contrast resolution. It is the aim, therefore, of the work proposed here to address the following issues in detail. 1.) Construct a heating source fully integrated with an ultrasound imaging system to provide controlled energy delivery to tissue equivalent phantoms and excised tissue samples during routine ultrasound scanning. Both ultrasound and microwave heating sources will be investigated. 2.) Develop robust pulse sequence and data acquisition schemes for controlled heating with simultaneous ultrasonic imaging. 3.) Develop signal processing methods to remove the effects of unwanted tissue motion during TSI data acquisition. Like all high precision speckle tracking methods, TSI is susceptible to tissue motion artifacts. Methods must be developed to identify and minimize these artifacts. 4.) Demonstrate that TSI can separate water-bearing tissues from lipids in images similar to methods developed for magnetic resonance imaging but with high spatial resolution for peripheral vascular applications. 5.) Demonstrate on excised arterial samples that TSI can identify the lipid pool within an arterial plaque. The results of these preliminary experiments will test TSI as an imaging technique for vulnerable plaque detection. If it proves viable, we will develop an RO1 proposal to build an integrated imaging system combining ultrasound with a controlled heat source and explore the possibility of noninvasive, in vivo highrisk plaque identification in the carotid and other peripheral arteries.